Primary central nervous system T-cell lymphoma in children and adolescents: a clinicopathological analysis of five cases / 中华病理学杂志

Objective: To study the clinicopathological characteristics, and further understand primary central nervous system T-cell lymphoma (PCNSTCL) in children and adolescents. Methods: Five cases of PCNSTCL in children and adolescents were collected from December 2016 to December 2021 at the First Affiliated Hospital of Zhengzhou University. The clinicopathological characteristics, immunophenotypic, and molecular pathologic features were analyzed, and relevant literatures reviewed. Results: There were two male and three female patients with a median age of 14 years (range 11 to 18 years). There were two peripheral T-cell lymphomas, not otherwise specified, two anaplastic large cell lymphoma, ALK-positive and one NK/T cell lymphoma. Pathologically, the tumor cells showed a variable histomorphologic spectrum, including small, medium and large cells with diffuse growth pattern and perivascular accentuation. Immunohistochemistry and in situ hybridization showed CD3 expression in four cases, and CD3 was lost in one case. CD5 expression was lost in four cases and retained in one case. ALK and CD30 were expressed in two cases. One tumor expressed CD56 and Epstein-Barr virus-encoded RNA. All cases showed a cytotoxic phenotype with expression of TIA1 and granzyme B. Three cases had a high Ki-67 index (>50%). T-cell receptor (TCR) gene rearrangement was clonal in two cases. Conclusions: PCNSTCL is rare, especially in children and adolescents. The morphology of PCNSTCL is diverse. Immunohistochemistry and TCR gene rearrangement play important roles in the diagnosis.

Brain Tumor Heterogeneity

Tumor heterogeneity is the concept that different tumor cells provide distinct biomorphological lesions, gene expressions, proliferation, microenvironment and graduated capacity of metastatic lesions. Brain tumor heterogeneity has been recently discussed about the interesting interaction of chronic inflammation, microenvironment, epigenetics and glioma steam cells. Brain tumors remain a challenge with regards to medication and disease, due to the lack of treatment options and unsatisfactory results. These results might be the result of the brain tumor heterogeneity and its multiple resistance mechanisms to chemo and radiotherapy.

Effect of Aloe vera on the expression of nerve factors, p75 and TrkA receptors in the hippocampus of diabetic rats / Efecto del Aloe vera sobre la expresión de factores de crecimiento nervioso, Receptores p75 y TrkA en el hipocampo de ratas diabéticas

SUMMARY: Diabetes mellitus can lead to structural disorders in the brain. One of the most common complications of diabetes, diabetic neuropathy is associated with central nervous system disorders. Aloe vera has anti-diabetic, antioxidant, and neuroprotective effects. This study was designed to evaluate the effects of Aloe vera gel on the hippocampus changes as well as the expression of nerve growth factor and receptors TrkA and P75 in the hippocampus of streptozotocin (STZ)-induced diabetic rats. 25 male Wistar rats were randomly divided into 5 groups including: control (normal saline), diabetic (normal saline), Aloe vera gel (400 mg/kg/day; gavage), diabetic + Aloe vera gel (400 mg/kg/day; gavage) and diabetic + insulin NPH (10 IU/kg/day; subcutaneous). Experimental diabetes was induced by streptozotocin injection (60 mg/kg; intraperitoneal). All groups treated for 8 weeks. At the end of treatment course, the rat brains were removed for measuring the expression of nerve growth factor, p75 and TrkA receptors were evaluated in the hippocampus. Diabetes induction after 8 weeks caused NGF and P75 expression levels in the diabetic group than other groups significantly increased (p<0.05). The TrkA receptor expression in the diabetic group compared with the control had a significant reduction (p<0.05). On the other hand in the diabetic group receiving Aloe vera gel expression of NGF and P75 expression levels compared to the diabetic group was significantly reduced (p<0.05) and the TrkA receptor expression compared with the diabetic group had a significant increase (p<0.05). The results showed that oral administration of Aloe vera gel in diabetic rats ameliorates diabetes-induced hyperglycemia. On the other hand, Aloe vera gel cause modulation of the expression of NGF neurotrophic factor via increased expression of TrkA receptor-specific and non-specific receptor down-regulation of P75 in the hippocampus of STZ-induced diabetic rats.

RESUMEN: La diabetes mellitus puede provocar trastornos estructurales en el cerebro. Es una de las complicaciones más comunes de la diabetes y la neuropatía diabética y está relacionada con trastornos del sistema nervioso central. El Aloe vera tiene efectos antidiabéticos, antioxidantes y neuroprotectores. Este estudio fue diseñado para evaluar los efectos del gel de Aloe vera en los cambios del hipocampo, así como la expresión del factor de crecimiento nervioso y los receptores TrkA y P75 en el hipocampo de ratas diabéticas inducidas por estreptozotocina (STZ). Se dividieron al azar 25 ratas Wistar macho en 5 grupos de: control (solución salina normal), diabéticos (solución salina normal), gel de Aloe vera (400 mg / kg / día; sonda), diabéticos + gel de Aloe vera (400 mg / kg / día; sonda) y diabéticos + insulina NPH (10 UI / kg / día; subcutánea). La diabetes experimental fue inducida por inyección de estreptozotocina (60 mg / kg; intraperitoneal). Todos los grupos fueron tratados durante 8 semanas. Al final del tratamiento, se extrajeron los cerebros de las ratas para medir la expresión del factor de crecimiento nervioso y se evaluaron los receptores p75 y TrkA en el hipocampo. La inducción de diabetes después de 8 semanas provocó que los niveles de expresión de NGF y P75 en el grupo de diabéticos aumentaran significativamente en comparación con otros grupos (p <0,05). La expresión del receptor TrkA en el grupo diabético comparado con el control tuvo una reducción significativa (p <0,05). Por otro lado, el grupo de ratas diabéticas que recibieron la expresión en gel de Aloe vera de NGF y los niveles de expresión de P75 en comparación con el grupo de ratas diabéticas se redujo significativamente (p <0,05) y la expresión del receptor de TrkA en comparación con el grupo de ratas diabéticas tuvo un aumento significativo (p <0,05). Los resultados mostraron que la administración oral de gel de Aloe vera en ratas diabéticas mejora la hiperglucemia inducida por la diabetes. Por otro lado, el gel de Aloe vera causa modulación de la expresión del factor neurotrófico NGF a través del aumento de la expresión de receptor TrkA específico y no específico y regulación negativa del receptor de P75 en el hipocampo de ratas diabéticas inducidas por STZ.

Research Progress of Discoidin Domain Receptor 1 in Breast Cancer and Other Malignant Tumors / 中国医学科学院学报

Discoidin domain receptor 1(DDR1)is a critical member of the receptor tyrosine kinase family.It may be related to tumor invasion and metastasis,and the abnormal activation of DDR1 can lead to the occurrence and development of malignant tumors,inflammation,and fibrosis.DDR1 are involved in cell adhesion,migration,proliferation,secretion of cytokines,and remodeling of extracellular matrix,thus playing a critical role in various pathophysiological processes of the human body.In this review,we demonstrate the research progress of DDR1 in breast cancer and other malignant tumors,in order to provide a new theoretical basis for the prevention and treatment of breast cancer and other tumors.

Efficacy of Pemetrexed-based Chemotherapy in Comparison to Non-Pemetrexed-based Chemotherapy in Advanced, ALK+ Non-Small Cell Lung Cancer

PURPOSE: Previous retrospective studies suggest that anaplastic lymphoma kinase (ALK) mutation-positive (ALK+) non-small cell lung cancer (NSCLC) patients are sensitive to pemetrexed. To determine its efficacy, we retrospectively evaluated clinical outcomes of pemetrexed-based chemotherapy in patients with ALK+ NSCLC. MATERIALS AND METHODS: We identified 126 patients with advanced, ALK+ NSCLC who received first-line cytotoxic chemotherapy. We compared response, progression-free survival (PFS), and overall survival (OS) rates according to chemotherapy regimens. Furthermore, we evaluated intracranial time to tumor progression (TTP) and proportion of ALK+ cells as prognostic factors. RESULTS: Forty-eight patients received pemetrexed-based chemotherapy, while 78 received other regimens as first-line treatment. The pemetrexed-based chemotherapy group showed superior overall response (44.7% vs. 14.3%, p < 0.001) and disease control (85.1% vs. 62.3%, p=0.008) rates. The pemetrexed-based chemotherapy group also exhibited longer PFS (6.6 months vs. 3.8 months, p < 0.001); OS rates were not significantly different. The lack of exposure to second-generation ALK inhibitors and intracranial metastasis on initial diagnosis were independent negative prognostic factors of OS. Intracranial TTP was similar between the treatment groups (32.7 months vs. 35.7 months, p=0.733). Patients who harbored a greater number of ALK+ tumor cells (≥70%) showed prolonged OS on univariate analysis (not reached vs. 44.8 months, p=0.041), but not on multivariate analysis (hazard ratio: 0.19, 95% confidence interval: 0.03–1.42; p=0.106). CONCLUSION: Pemetrexed-based regimens may prolong PFS in patients with ALK+ NSCLC as a first-line treatment, but are not associated with prolonged OS. Exposure to second-generation ALK inhibitors may improve OS rates in patients with ALK+ NSCLC.

Peptide Nucleic Acid Clamping and Direct Sequencing in the Detection of Oncogenic Alterations in Lung Cancer: Systematic Review and Meta-Analysis

PURPOSE: Molecular testing in non-small cell lung cancer (NSCLC) aids in identifying oncogenic alterations. The aim of this study was to compare the rates of detection of oncogenic alterations and responsiveness to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) according to EGFR mutation status as determined by peptide nucleic acid (PNA) clamping or direct sequencing (DS). MATERIALS AND METHODS: We performed a systematic literature search using MEDLINE, EMBASE, and the Cochrane Central Register. Data from included studies were pooled to yield summary sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds ratio, and receiver operating characteristic curves. A meta-regression analysis was conducted to identify potential sources of heterogeneity between selected studies. RESULTS: We identified 10 studies comprising 924 patients. Oncogenic alterations were detected in 340 of 924 cases (36.8%) with PNA clamping and in 250 of 924 (27.1%) with DS. The pooled sensitivities of PNA clamping and DS were 0.93 [95% confidence interval (CI): 0.90−0.95] and 0.69 (95% CI: 0.64−0.73), respectively. According to meta-regression analysis, none of the covariates were found to be significant sources of heterogeneity. With respect to treatment responses to EGFR-TKIs, there was no significant difference therein between EGFR mutations detected by PNA clamping and DS (53.4% vs. 50.8%; risk ratio, 0.99; 95% CI 0.83−1.19; p=0.874). CONCLUSION: We demonstrated that PNA clamping has a higher sensitivity than DS for detecting oncogenic alterations in NSCLC. Our findings suggest that PNA clamping is a more useful method for clinical practice.

Association among measures of mobility-related disability and self-perceived fatigue among older people: a population-based study

Objective: To investigate the relationship between self-perceived fatigue with different physical functioning tests and functional performance scales used for evaluating mobility-related disability among community-dwelling older persons. Method: This is a cross-sectional, population-based study. The sample was composed of older persons with 65 years of age or more living in Cuiabá, MT, and Barueri, SP, Brazil. The data for this study is from the FIBRA Network Study. The presence of self-perceived fatigue was assessed using self-reports based on the Center for Epidemiologic Studies-Depression Scale. The Lawton instrumental activities of daily living scale (IADL) and the advanced activities of daily living scale (AADL) were used to assess performance and participation restriction. The following physical functioning tests were used: five-step test (FST), the Short Physical Performance Battery (SPPB), and usual gait speed (UGS). Three models of logistic regression analysis were conducted, and a significance level of α<0.05 was adopted. Results: The sample was composed of 776 older adults with a mean age (SD) of 71.9 (5.9) years, of whom the majority were women (74%). The prevalence of self-perceived fatigue within the participants was 20%. After adjusting for covariates, SPPB, UGS, IADL, and AADL remained associated with self-perceived fatigue in the final multivariate regression model. Conclusion: Our results suggest that there is an association between self-perceived fatigue and lower extremity function, usual gait speed and activity limitation and participation restriction in older adults. Further cohort studies are needed to investigate which physical performance measure may be able to predict the negative impact of fatigue in older adults. .

Emancipatory practices of nurses in primary health care: the home visit as an instrument of health needs assessment / Prácticas emancipadoras del enfermero en la atención primaria de salud: la visita domiciliaria como instrumento de reconocimiento de necesidades de la salud / Práticas emancipatórias de enfermeiros na Atenção Básica à Saúde: a visita domiciliar como instrumento de reconhecimento de necessidades de saúde

Objective Identify nurses’ emancipatory practices in primary care, to contribute to the improvement of health care. Method A case study type social research of qualitative nature, in which nurses of a primary health care service unit in São Paulo were interviewed. Results The home visit was identified as a nursing practice possible to be expanded in order to identify social determinants of health, triggering emancipatory practices in the service. This expansion occurred because the design of health care labour intended by the service team changed its focus from the traditional object of health services, the disease. Conclusion First, it is advocated that social policies lead projects with the purpose of improving health needs. On the other hand, the daily labour needs to provide opportunities for reflection and discussion of healthcare projects, leading workers to propose labour-processes targeted to both the social determinants of health and people’s illness. .

Objetivo Identificar las prácticas emancipadoras de enfermeras en Unidad de Salud Familiar fueron el objeto de este estudio. Método La investigación social cualitativa tipo estúdio de caso. Fueron entrevistados enfermeros de una Unidad de Salud Familiar en Sao Paulo. Resultados Se identificó que la Visita Domiciliaria ha ampliado su alcance y identificado determinantes del proceso salud-enfermedad, lo que provocó en la Unidad de Salud Familiar prácticas emancipadoras. Esta expansión se produjo debido a que el diseño de la atención en propósito por la USF amplió el tradicional objeto de los servicios de salud. Conclusión Se aboga que las directrices de las políticas sociales basen proyectos que tengan como fin el mejoramiento de las necesidades de salud y que el trabajo diario proporcione la reflexión y discusión de los proyectos de atención, para proponer prácticas que enfoquen en los determinantes del proceso salud-enfermedad, tanto cuanto en sus resultados - la enfermedad en el cuerpo individual. .

Objetivo Identificar as práticas emancipatórias de enfermeiros da Atenção Primária, com a finalidade de contribuir para o aprimoramento do cuidado em saúde. Método Pesquisa social de natureza qualitativa, do tipo estudo de caso. Foram entrevistados os enfermeiros de uma Unidade de Saúde da Família em São Paulo. Resultados Identificou-se que a visita domiciliária, prática protocolar, ampliou seu escopo e identificou determinantes do processo saúde-doença, desencadeando na Unidade de Saúde da Família práticas emancipatórias. Essa ampliação ocorreu porque o projeto de cuidado intencionalizado ampliou o objeto tradicional dos serviços de saúde. Conclusão Advoga-se que as diretrizes das políticas sociais ancorem projetos que tomem como finalidade o aprimoramento das necessidades de saúde e que o cotidiano do trabalho proporcione reflexão e discussão dos projetos de cuidado, para intencionalizar práticas que incidam nos determinantes do processo saúde-doença, tanto quanto nos resultados - a doença expressa no corpo individual. .

Effect of missense mutations on structure and interaction of anaplastic lymphoma kinase [ALK] in neuroblastoma

Neuroblastoma is a cancer of the sympathetic nervous system, accounting for upto 15% of childhood cancer mortality. It can occur in many areas but most of them begin in the abdomen in the adrenal gland and can spread to the bones and other areas. http:/en.wikipedia.org/wiki/Neuroblastoma-cite_note-pmid19383347-3. Unfortunately, like other cancers, its causes are still poorly understood. Anaplastic lymphoma kinase [ALK], a membrane associated tyrosine kinase was recently found to be mutated in neuroblastoma. Protein sequence of ALK was retrieved from UniProt and the seven identified mutations were substituted in native sequence to get its mutant proteins. Significant changes were explored in the mutant secondary structures when compared with the native protein. Changes were also observed in the physiochemical properties and it can therefore be inferred that, these changes may be translated in the tertiary structures due to their effects on the folding pattern. Tertiary structure of the protein modeled after refinement and validation was submitted to Protein Model Database [PMDB] and was assigned with the PMDB ID P0077827. RMSD values of the mutant structures were observed deviated from the native structure when compared with probability < 0.05. It was observed that there are a total of 15 Disordered Regions in the protein having a total of 290 Disordered Residues. Protein-ligand interaction analysis was performed to investigate the effects of mutations damaging its interactions and it was observed that the mutations understudy affects its interactions with ATP which ultimately results in causing neuroblastoma. This study was based on the in silico mutation analysis of Seven missense mutations of anaplastic lymphoma kinase which can better explain why missense mutations in ALK protein cause neuroblastoma. Structure and sequence based computations were systematically and comprehensively evaluated applied to the mutants in anaplastic lymphoma kinase and on the basis of our observations a detailed structural explanations have been developed for the measured and predicted impact of these missense substitutions

G691S/S904S polymorphism in the RET protooncogene of a 25-year-old medical student with bilateral pheochromocytoma.

The case of a 25-year-old medical student with bilateral pheochromocytoma is described. Following diagnostic testing, tumors were surgically removed. Genetic analysis revealed that the patient is a heterozygote with the following mutations on opposite homologs: G691S (exon 11) and S904S (TCC-TCG, exon 15), suggesting the diagnosis of multiple endocrine neoplasia 2A (MEN2A). A diagnosis of MEN2 would be an indication of thyroidectomy in this patient. Although this mutation is described in the literature, it has no known connection to pheochromocytomas. Therefore, it is unknown whether there is a causal connection between the G691S genotype and the pheochromocytomas in this patient. If so, G691S is to be added to the list of genotypes causing MEN2A. Here, the procedure of sequencing the RET protooncogene is described and a possible association between the G691S genotype and MEN2A is discussed.

Molecular genetics of papillary thyroid carcinoma: great expectations...

Papillary thyroid carcinoma (PTC) is the most prevalent type of endocrine cancer and, in recent epidemiological surveys, one of the types of human cancer whose incidence is growing. Despite the favourable outcome and long survival rates of most patients, some tumours display an aggressive behaviour and may progress to the highly aggressive and lethal, anaplastic thyroid carcinoma. In recent years, several progresses have been made on the molecular characterization of PTC, in general, and in the genetic alterations underlying the histotype diversity of this type of cancer, in particular. This holds true regarding alterations on nuclear DNA as well as mitochondrial DNA. In this review we have summarized the most recent findings in the genetic characterization of PTC, giving a particular emphasis to the genotype-phenotype associations, the prognosis implications, and the diagnostic and therapeutic value of the newly identified genetic markers.

O carcinoma papilífero de tireóide (CPT) é o tipo mais prevalente de câncer endócrino e, em pesquisas epidemiológicas recentes, um dos tipos de câncer humano cuja incidência vêm crescendo. A despeito do prognóstico favorável e da longa taxa de sobrevivência da maioria dos pacientes, alguns tumores mostram um comportamento agressivo e podem progredir para o altamente agressivo e letal carcinoma anaplásico de tireóide. Recentemente, vários progressos foram feitos quanto à caracterização molecular do CPT, em general, e às alterações genéticas subjacentes à diversidade histológica desse tipo de câncer, em particular, particularmente com respeito às alterações dos DNAs nuclear e mitocondrial. Nesta revisão, nós sumarizamos os achados mais recentes da caracterização genética do CPT, dando ênfase particular às associações genótipo-fenótipo, às implicações prognósticas e ao valor diagnóstico e terapêutico dos marcadores genéticos recentemente identificados.

Patogênese dos tumores diferenciados da tiróide (papilífero e folicular) / Pathogenesis of differentiated thyroid cancer (papillary and follicular)

Os carcinomas diferenciados da tiróide, o papilífero (PTC) e o folicular (FTC) são as neoplasias endócrinas mais comuns. Descobertas recentes esclareceram diversos aspectos de sua patogênese, analisados nesta revisão. No PTC, uma única mutação no gene BRAF (o gene da Raf quinase tipo B) (V600E) é responsável pela doença em 40-50% dos pacientes, especialmente os mais velhos e os que apresentam subtipos histológicos mais agressivos. Tendo em vista esses fatores prognósticos da mutação BRAF, o uso de sua pesquisa no material proveniente do exame citológico de tiróide pode ser útil para fins de diagnóstico e conduta. A outra causa freqüente de PTC são os rearranjos RET/PTC, decorrentes da quebra e fusão do domínio TK intra-celular de RET com fragmentos 5’ de diversos genes, resultando num gene quimérico que produz uma proteína que apresenta atividade constitutiva de uma tirosina quinase de RET, presentes em 20-30% dos pacientes, especialmente os mais jovens ou que receberam radiação. Já a patogênese do FTC é menos compreendida. Descreve-se a participação do gene decorrente da fusão entre PAX8 e PPARg (peroxisome proliferator-activated receptor g) em 30-50% dos pacientes com este tumor; entretanto, esta fusão pode ocorrer também em adenomas foliculares. Desta forma, ainda não há evidência completa de que PAX8-PPARg seja a causa do FTC. Outro achado no FTC são as mutações no gene RAS; quando ocorrem mutações do RAS não acontece o rearranjo PAX8-PPARg. Outra possível causa de FTC é a perda ou expressão exagerada de uma série de genes, alguns demonstrados por técnicas de expressão diferencial de genes, como TRg, PTEN, PKAR1A, DDIT3, ARG2, ITM1 e C1orf24.

Prenatal exclusion of Crouzon syndrome by mutation analysis of FGFR2.

Crouzon Syndrome is an autosomal dominant syndromic craniosynostosis characterized by premature closure of cranial sutures, exophthalmos, and midface hypoplasia. It is caused by multiple mutations in the fibroblast growth factor receptor 2 (FGFR2). We describe prenatal genetic testing of FGFR2 in a fetus of a mother whose previous child had Crouzon Syndrome due to an apparently de novo mutation, S351C. Sequence electropherograms of the exon 10 of FGFR2 encompassing the codon 351 revealed only the normal sequence, thus predicting a very high likelihood of an unaffected fetus. The study was confirmed by the birth of a normal neonate. We report the use of molecular genetic testing to exclude Crouzon Syndrome due to FGFR2 mutation prenatally. Prenatal diagnostic testing for a known mutation is a reasonable option for couples at risk for having a child with Crouzon Syndrome due to germline mosaicism. Molecular testing is more accurate and reliable than ultrasonography and provides families with reassurance.

A RET C634R mutation in a Thai female with multiple endocrine neoplasia type 2A.

Multiple endocrine neoplasia type 2A (MEN 2A) is an autosomal dominant disorder characterized by medullary thyroid carcinoma, pheochromocytoma and primary hyperparathyroidism. The first tumor is usually a medullary thyroid carcinoma. MEN 2A is caused by mutations in the RET proto-oncogene. The detection of mutations in the gene has important diagnostic and therapeutic impacts. Genetic testing of at-risk family members allows one to identify individuals carrying the mutant alleles with very high specificity and sensitivity. Subsequently, total thyroidectomy, recommended at 5 years of age, can be performed in a prophylactic attempt. The authors performed a molecular analysis to identify a mutation in a Thai woman with MEN 2A. She was found to be heterozygous for 1900T>C (C634R). The patient had two daughters who were not found to carry the mutation. The newly available genetic test for patients with MEN 2A in Thailand makes possible accurate DNA-based diagnosis of their at-risk family members before development of the disease, which has important therapeutic impacts for them.

A case of Pfeiffer syndrome type 1 with an A344P mutation in the FGFR2 gene.

Pfeiffer syndrome, an autosomal dominant disorder, consists of craniosynostosis, broadening of the thumbs and great toes, and partial soft tissue syndactyly of the hands and feet. Three clinical subtypes have been classified mainly for the purpose of genetic counseling. Mutations in FGFR1 and FGFR2 are known to be associated with the syndrome. However, the correlation between genotype and phenotype is not well defined. Only one patient with Pfeiffer syndrome with no other clinical information has been reported to have had an A344P mutation of the FGFR2. Here we report a Thai male patient with sporadic Pfeiffer syndrome type 1 with impaired intelligence (IQ = 77). Mutation analysis revealed A344P in FGFR2. Identification of the clinical features and molecular defects in more patients is required to better correlate the genotype and phenotype of this complex syndrome.